Cardiac arrest, also known as cardiopulmonary arrest, is an abrupt cessation of pump function in the heart, and cessation of normal circulation of the blood due to failure of the heart to contract effectively. Cardiac arrest can be caused by a variety of factors including, e.g., coronary heart disease, hypertension, myocardial infarction and ischemia, atrial and ventricular arrhythmias, and heart failure.
Cardiac arrest is potentially reversible if treated early. However, if untreated, unexpected cardiac arrest can lead to death within minutes. The treatment for cardiac arrest is immediate defibrillation while cardiopulmonary resuscitation (CPR) is used to provide circulatory support. Defibrillation is performed by applying an electric shock to the heart, which resets the cells, permitting a normal beat to re-establish itself. CPR is a critical part of the management of cardiac arrest. It should be started as soon as possible and interrupted as little as possible. The component of CPR which seems to make the greatest difference is the chest compressions.
Despite significant progress in CPR methods in recent decades, survival following sudden cardiac arrest due to ventricular arrhythmias (“VA”), e.g., ventricular tachycardia (“VT”) and/or ventricular fibrillation (“VF”), and subsequent advanced life support has not dramatically improved.1 Survival from out-of-hospital cardiac arrest to hospital admission is estimated to be 23.8% with only 7.6% survival to hospital discharge.1 Strategies for increasing survival by using adjunctive treatment and interventions such as beta-blockers or certain antiarrhythmic agents have been attempted with little success.1-4 Shock resistant VF, refibrillation, post-shock pulseless electrical activity, and decreased myocardial contractility after resuscitation are challenges frequently observed during resuscitation from VF. Many of these factors have been shown to affect survival and morbidity.1,4-6 
VAs are characterized by a disruption in the normal excitation-contraction rhythm of heart. In particular, VT and VF are characterized by abnormally rapid, asynchronous contraction of the ventricles. As such, the heart is unable to adequately pump oxygenated blood to the systemic circulation. If not treated immediately, VAs can lead to additional tissue damage or patient death. These potentially life threatening events are characterized by, among other things, an increase in transient calcium currents and an elevation in diastolic calcium concentration in cardiac tissue, lengthening of the cardiac action potential, a drop in blood pressure and ischemia (lack of adequate blood flow to the heart). These changes can potentially affect the return of spontaneous circulation, hemodynamics, refibrillation and resuscitation success.
Resistant ventricular fibrillation, refibrillation and diminished myocardial contractility are important factors leading to poor survival following cardiac arrest. Global ischemia from VF arrest activates multiple pathways, which leads to dysfunction of several ion channels including calcium cycling channels amongst others. For example, VA events may lead to calcium overload and myocardial dysfunction after prolonged VT or VF.
Previous studies have suggested that the cardiac-specific Ryanodine Receptor, RyR2, dysfunction diminishes cardiac contractility in a manner that is analogous to that observed in heart failure in both human and animal models.8-10 It is proposed that a “leaky” ryanodine receptor underlies the initiation and maintenance of VT or VF.9,11 Previous in vitro studies have suggested that prior administration of dantrolene soldium can stabilize RyR2 and confer resistance to the induction of arrhythmias. However, it is unknown whether RyR2 dysfunction can be rectified in response to, or subsequent to a VT or VF event in order to acutely treat or control arrhythmias, e.g., arrhythmias that occur subsequent to cardiac arrest. Furthermore, it is unknown whether such acute treatments can impart any protection from additional, potentially fatal arrhythmic events in order to improve hemodynamic outcomes and patient survival.
Thus, a need remains in the art for therapeutic agents and methods effective for the acute treatment of cardiac arrhythmias, e.g., ventricular arrhythmias such as VT and/or VF, such as occur following, e.g., atrial fibrillation, premature ventricular contraction, infarction, ischemia, tachycardia, heart failure or cardiac arrest. Moreover, there exists a need in the art for therapeutic interventions that prevent or abrogate additional or subsequent arrhythmias and to ameliorate their detrimental effects.